Acute pain has been characterized as a normal sensation triggered in the nervous system to alert the individual to possible injury. Chronic (neuropathic) pain, on the other hand, is a persistent discomfort in which pain signals reverberate in the nervous system for prolonged periods of time (e.g., weeks, months, or years). Chronic pain may be initiated by an initial traumatic event, such as a sprained back, a serious infection, neurologic or nerve injury and the like, or there may be an ongoing root cause of pain, such as arthritis, cancer, or inflammation. Some people suffer from chronic pain even in the absence of any past injury or evidence of bodily damage. Common chronic pain conditions include headaches, low back pain, cancer pain, arthritis pain, neurogenic pain (i.e., pain resulting from damage to the peripheral nerves or to the central nervous system itself), and psychogenic pain (pain not due to past disease or injury or any visible sign of damage inside or outside the nervous system).
A variety of treatments have been proposed and evaluated for the treatment of chronic pain, including medications, acupuncture, local electrical stimulation, brain stimulation, and surgery. Psychotherapy, relaxation therapy, biofeedback, and behavior modification have also been employed in attempts to treat chronic pain. Despite the many proposed therapies, chronic pain remains an important and increasingly common medical complaint, the root causes of which are often difficult to determine, and which frequently are difficult to treat and control.
Studies on the cellular and molecular mechanisms of chronic pain syndromes have focused attention on maladapted activity of voltage sensitive sodium channels in chronic pain syndromes, e.g., over activity of signal conduction mediated by the voltage sensitive sodium channels in the pain sensitive neurons. The other major biologic system implicated in origination of chronic pain is the N-methyl-D-aspartate (NMDA) receptors e.g., overactive signal transduction mediated by the NMDA subtype of glutamatergic receptors in the CNS is an important manifestation of chronic pain.
There is an ongoing need for methods of treating chronic neuropathic pain. The present invention provides methods for treating chronic pain utilizing diarylureido-dihalokynurenate compounds that reduce the activity of sodium channels in a use-dependent manner and target the NMDA receptor through its glycine binding site.